JP4332353B2 - Composition for treatment of drug-induced constipation comprising 15-keto-prostaglandins - Google Patents

Description

  The present invention relates to a novel use for the treatment of drug-induced constipation of 15-keto-prostaglandin compounds.

  Constipation is classified into functional constipation such as flaccid constipation, spastic constipation and rectal constipation, organic constipation caused by bowel disease and stenosis due to adhesion after surgery, and drug-induced constipation.

  Drug-induced constipation is constipation that occurs as a side effect due to the use of drugs. In addition, the drug may cause constipation indirectly rather than directly. For example, the stool becomes hard due to the drainage of water from the body by a diuretic and causes constipation. Furthermore, although one type of drug does not cause constipation, constipation may occur due to an additive or synergistic effect of a combination of a plurality of drugs.

Drugs that cause constipation include narcotics (opioid narcotics such as morphine and codeine) used to control cancer pain, anticholinergics (parkinson's disease therapeutic agents, tricyclic and tetracyclic antidepressants) , Antacids (aluminum preparations, etc.), bone mass increasing agents (calcium preparations, etc.), diuretics, iron agents, calcium antagonists, benzodiazepine compounds, phenothiazine compounds (chlorpromazine, etc.) , H 2 _- blockers, pill, etc. tocopherols are known.

  For example, opioids such as morphine, which is a type of narcotic, have an inhibitory action (analgesic, antitussive, sedative, hypnotic etc.) on the central nervous system, and the analgesic action is extremely powerful, so almost all pain, For example, it is effective for surgical pain and cancer pain, but on the other hand, it acts on the gastrointestinal tract as a peripheral action and exhibits antipruritic action. Thus, for example, when morphine is used to treat pain, constipation develops in almost all patients who have been administered morphine, and stubborn constipation occurs if neglected. Constipation is expressed by the amount of morphine necessary for exerting analgesic action and is difficult to tolerate. Therefore, constipation continues by morphine administered by any route as long as administration continues. For example, even if morphine is used as an analgesic measure for cancer patients, if constipation measures are insufficient, morphine administration cannot be maintained, and the treatment results for cancer pain will deteriorate. For this reason, when morphine is repeatedly administered, reliable prevention of constipation is extremely important.

  However, it has been reported that constipation due to opioids such as morphine is often not well controlled by conventional laxatives (Twycross, RG et al .: Constipation. In: Control of alimentary symptoms in far advanced cancer. Edinburgh: Churchill Livingstone 1986: 172-177, which is incorporated herein by reference).

  Therefore, in recent years, opioid antagonists such as naloxone have been studied to improve opioid-induced constipation even if the analgesic action of the opioid is sacrificed to some extent. When opioid antagonists are used for opioid constipation, side effects have been reported that contradict the original purpose of opioid administration, such as return of pain and opioid withdrawal (Culpepper). -Morgan, JA et. Al .: NIDA Res. Monoger. 95: 399-400, 1989. and Clin. Pharamacol. Ther. 52: 90-95, 1992 .: Sykes, NP: Palliat-Med. 10: 135 -144, 1996. These references are incorporated herein by reference).

  Therefore, it is desired to develop a drug for improving drug-induced constipation without impairing the main action of the drug (for example, analgesic action of opioids such as morphine).

Prostaglandins (hereinafter referred to as PG (s)) are a group of organic carboxylic acids that are contained in human and other mammalian tissues or organs and exhibit a wide range of physiological activities. Naturally occurring PGs (natural PGs) generally have a prostanoic acid skeleton represented by the formula (A).

On the other hand, some synthetic analogs of natural PGs have a modified backbone. Natural PGs are classified into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structural characteristics of the five-membered ring part, and the carbon chain part These are classified into the following three types according to the number and position of unsaturated bonds.
Subscript 1: 13,14-unsaturated-15-OH
Subscript 2: 5,6- and 13,14-diunsaturated-15-OH
Subscript 3: 5,6-, 13,14- and 17,18-triunsaturated-15-OH.

  Furthermore, PGFs are classified into α (hydroxyl group is in an alpha configuration) and β (hydroxyl group is in a beta configuration) according to the arrangement of the 9th hydroxyl group.

PGE ₁ , PGE ₂ and PGE ₃ are known to have vasodilation, blood pressure lowering, decreased gastric secretion, increased intestinal motility, uterine contraction, diuresis, bronchodilation and anti-ulcer activity. PGF _1α , PGF _2α, and PGF _3α are known to have blood pressure increase, vasoconstriction, intestinal hypermotility, uterine contraction, luteal regression, and tracheal contraction characteristics.

  In addition, some 15-keto-PGs (ie, having an oxo group at position 15 instead of a hydroxyl group) and 13,14-dihydro-15-keto-PGs are present during the in vivo metabolism of natural PGs. It is known as a substance that is naturally produced by the action of enzymes. Further, 15-keto-PG compounds are disclosed in US Pat. No. 5,073,569, US Pat. No. 5,166,174, US Pat. No. 5,221,763, US Pat. No. 5,212,324, US Pat. No. 5,739,161, etc. Included in this application).

It is known that so-called natural PGs having a hydroxyl group at the 15-position, such as PGE ₁ , PGE ₂ and derivatives or analogs thereof, antagonize the gastrointestinal action of morphine (Christmas AJ: Prostaglandins 18, 279-284, 1979. B J. Broughton: Prostaglandin 22, 53-64, 1981. These references are incorporated herein by reference).

However, PGE ₁ and PGE ₂ are well known as substances that promote pain, and enhance the action of bradykinin, which is a powerful analgesic substance, and other analgesic substances. Therefore, so-called natural PGs having a hydroxyl group at the 15-position have the potential to affect the analgesic action of opioids.

  On the other hand, it is known that a 15-keto-16-halogen-PG compound is useful as a laxative (US Pat. No. 5,317,032). However, it is not known at all what kind of action the 15-keto-PG compound has on opioid-induced constipation, and how it affects the main action of drugs, such as analgesic action of opioids.

  An object of the present invention is to provide a composition for treating drug-induced constipation having a strong antagonism against drug-induced constipation without substantially impairing the main action of the drug.

  As a result of intensive studies on the biological activity of 15-keto-prostaglandin compounds, the present inventor has found that 15-keto-prostaglandin compounds have excellent antagonism against drug-induced constipation. In particular, this compound is extremely effective in controlling opioid-induced constipation because it has an excellent antagonistic effect on opioid-induced constipation without affecting the analgesic effect on the central nervous system of opioids such as morphine. As a result, the present invention has been completed.

  That is, the present invention relates to a composition for treating drug-induced constipation comprising a 15-keto-prostaglandin compound as an active ingredient.

  The present invention also provides drug-induced constipation comprising administering an effective amount of a 15-keto-prostaglandin compound to a subject suffering from or likely to suffer from drug-induced constipation. It relates to the treatment method.

  Furthermore, the present invention relates to the use of a 15-keto-prostaglandin compound for the manufacture of a pharmaceutical composition for the treatment of drug-induced constipation.

  In the present invention, “15-keto-prostaglandin compound (hereinafter abbreviated as“ 15-keto-PG compound ”)” means a five-membered ring structure, the number of double bonds on the α chain and ω chain, In addition, all derivatives or analogs (including substituents) of a compound having an oxo group instead of a hydroxyl group at the 15-position of the prostanoic acid skeleton are included regardless of the presence or absence of substituents and deformation of the upper chain part.

  In naming the 15-keto-PG compound of the present invention, the number of prostanoic acid shown in the above formula (A) is used.

  The formula (A) has a basic skeleton of C-20, but the number of carbon atoms in the 15-keto-PG compound in the present invention is not limited thereto. That is, in the formula (A), the number of the carbon constituting the basic skeleton of the PG compound is 1, with the carboxylic acid being 1, and in order toward the 5-membered ring, from 2 to 7 in turn to carbon on the α chain, and from 8 to 12 to 5 member Ring carbons with 13 to 20 on the ω chain, but when the carbon number decreases on the α chain, the number is deleted sequentially from the 2nd position, and the carbon number increases on the α chain The compound is named as having a substituent at the 2-position instead of the carboxyl group (1-position). Similarly, when the carbon number decreases on the ω chain, the carbon number is sequentially decreased from the 20th position, and when the carbon number increases on the ω chain, the 21st and subsequent carbon atoms are named as substituents. Moreover, regarding the configuration of the compound, unless otherwise specified, the configuration of the above formula (A) is followed.

  For example, PGD, PGE, and PGF refer to PG compounds having a hydroxyl group at the 9-position and / or 11-position, but in this specification, those having other groups instead of the 9-position and / or 11-position hydroxyl groups. Is also included. When naming these compounds, they are named in the form of 9-dehydroxy-9-substituted-PG compounds or 11-dehydroxy-11-substituted-PG compounds. A PG compound having hydrogen instead of a hydroxyl group is simply referred to as a 9- or 11-dehydroxy compound.

  As described above, in the present invention, the 15-keto-PG compound is named based on the prostanoic acid skeleton. However, when the compound has a partial structure similar to prostaglandin, “PG” is used for the sake of brevity. The abbreviation may be used. In this case, a PG compound in which the number of carbon atoms in the α chain is extended by 2, that is, a PG compound having 9 carbon atoms in the α chain is 2-decarboxy-2- (2-carboxyethyl) -15-keto-PG. Named compound. Similarly, a PG compound having 11 carbon atoms in the α chain is named 2-decarboxy-2- (4-carboxybutyl) -15-keto-PG compound. A PG compound in which the number of carbon atoms in the ω chain is extended by 2, that is, a PG compound having 10 carbon atoms in the ω chain is named 15-keto-20-ethyl-PG compound. The naming can be performed based on the IUPAC nomenclature.

  The 15-keto-PGs used in the present invention may be any PG derivative or analog having an oxo group instead of a hydroxyl group at the 15-position, and a 15-keto-PG having one double bond at the 13-14 position. Type 1 compounds, 15-keto-PG type 2 compounds with two double bonds at positions 13-14 and 5-6, three 2 at positions 5-6, 13-14 and 17-18 Examples include 15-keto-PG type 3 compounds having a heavy bond, or 13,14-dihydro-15-keto-PG compounds in which the double bond at positions 13-14 of these compounds is a single bond. The

  Examples of representative compounds that can be used in the present invention are 15-keto-PG type 1, 15-keto-PG type 2, 15-keto-PG type 3, 13,14-dihydro-15-keto-PG type 1. 13,14-dihydro-15-keto-PG type 2, 13,14-dihydro-15-keto-PG type 3 and the like and derivatives or analogs thereof.

  Examples of analogs (including substituents) or derivatives include compounds in which the α-chain terminal carboxyl group of the 15-keto-PG compound is esterified, compounds in which the α-chain terminal skeletal carbon number is extended, physiologically An acceptable salt, a compound in which the carbon bond at the 2-3 position has a double bond or the carbon bond at the 5-6 position has a triple bond, the 3rd, the 5th, the 6th, the 16th, the 17th, the 18th, A compound having a substituent at the 19th and / or 20th carbon, a compound having a lower alkyl group or a hydroxy (lower) alkyl group in place of the 9th and / or 11th hydroxyl group.

  In the present invention, examples of suitable substituents bonded to the 3-position, 17-position, 18-position and / or 19-position carbon atom include an alkyl group having 1 to 4 carbon atoms, particularly a methyl group and an ethyl group. It is done. Suitable examples of the substituent bonded to the 16th carbon atom include a lower alkyl group such as a methyl group and an ethyl group, a hydroxyl group or a halogen atom such as chlorine and fluorine, and an aryloxy group such as trifluoromethylphenoxy. Suitable examples of the substituent at the 17th carbon atom include a lower alkyl group such as a methyl group and an ethyl group, a hydroxyl group or a halogen atom such as chlorine and fluorine, and an aryloxy group such as trifluoromethylphenoxy. Suitable substituents bonded to the 20th carbon atom include saturated or unsaturated lower alkyl groups such as C1-4 alkyl, lower alkoxy groups such as C1-4 alkoxy, C1-4 alkoxy-C1-4, and the like. Including lower alkoxyalkyl such as alkyl. Suitable substituents for the 5-position carbon atom include halogen atoms such as chlorine and fluorine. Suitable substituents on the 6-position carbon atom include oxo groups that form carbonyl groups. The configuration of PGs having a hydroxy group, a lower alkyl or a hydroxy (lower) alkyl substituent at the 9th and / or 11th carbon atom may be α, β or a mixture thereof.

  Further, the analog or derivative is a compound having a substituent such as an alkoxy group, a cycloalkyl group, a cycloalkyloxy group, a phenoxy group or a phenyl group at the end of the ω chain of a compound having a shorter ω chain than natural PGs. Also good.

  Particularly preferred compounds are 13,14-dihydro-15-keto-PG compounds in which the carbon bond at positions 13-14 is a single bond, and one or two halogen atoms such as chlorine and fluorine at the carbon at position 16. Compound (15-keto-16 mono- or di-halogen-PG compound) having an oxo group at the 9-position carbon of the 5-membered ring and a compound having a hydroxyl group at the 11-position carbon (15-keto-PGE compound) It is done.

Preferred compounds used in the present invention are represented by the following formula (I):

Wherein L, M and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl or oxo (wherein at least one of the L and M groups is a group other than hydrogen; The 5-membered ring may have at least one double bond);
A represents —CH ₂ OH, —COCH ₂ OH, —COOH or a functional derivative thereof;
B is —CH ₂ —CH ₂ —, —CH═CH— or —C≡C—;
R ₁ is a divalent saturated or unsaturated low to intermediate aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocycle, and in aliphatic hydrocarbons At least one carbon atom may be optionally substituted with oxygen, nitrogen or sulfur;
Ra is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic or heterocyclic oxy, saturated or Unsaturated low to intermediate aliphatic hydrocarbon residue; cyclo (lower) alkyl group; cyclo (lower) alkyloxy group; aryl group; aryloxy group; heterocyclic group;

Of the above compounds, a particularly preferred group of compounds is represented by formula (II):

Wherein L and M are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl or oxo (wherein at least one of the groups L and M is a group other than hydrogen, The ring may have at least one double bond);
A represents —CH ₂ OH, —COCH ₂ OH, —COOH or a functional derivative thereof;
B is —CH ₂ —CH ₂ —, —CH═CH— or —C≡C—;
X ₁ and X ₂ are hydrogen, lower alkyl or halogen;
R ₁ is a divalent saturated or unsaturated low to intermediate aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocycle, and in aliphatic hydrocarbons At least one carbon atom may be optionally substituted with oxygen, nitrogen or sulfur;
R ₂ is a single bond or lower alkylene; and
R ₃ is lower alkyl, lower alkoxy, cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic or heterocyclic oxy].

In the above formula, the term “unsaturated” in R ₁ and Ra means that at least one or more double bonds and / or triple bonds are isolated as a bond between main chain and / or side chain carbon atoms. , Means containing separately or sequentially. In accordance with normal nomenclature, unsaturation between two consecutive positions is indicated by displaying the lower position number, and unsaturation between two non-consecutive positions is indicated by displaying both position numbers.

The term “low to intermediate aliphatic hydrocarbon” means a hydrocarbon having a straight or branched chain having 1 to 14 carbon atoms (however, the side chain is preferably one having 1 to 3 carbon atoms), preferably Is a hydrocarbon having 1 to 10 carbon atoms, particularly 6 to 10 carbon atoms in the case of R ₁ , and a hydrocarbon having 1 to 10 carbon atoms, particularly 1 to 8 carbon atoms, in the case of Ra.

  The term “halogen” includes fluorine, chlorine, bromine and iodine.

  The term “lower” includes groups having 1 to 6 carbon atoms unless otherwise specified in this specification.

  The term “lower alkyl” includes straight or branched chain saturated hydrocarbon groups of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

  The term “lower alkylene” refers to a straight or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms, such as methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butylene, pentylene and hexylene. including.

  The term “lower alkoxy” means lower alkyl-O—, wherein lower alkyl is as defined above.

  The term “hydroxy (lower) alkyl” means lower alkyl as described above substituted with at least one hydroxy group, for example hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1- Hydroxyethyl.

  The term “lower alkanoyloxy” means a group represented by the formula RCO—O—, wherein RCO— is an acyl formed by oxidation of a lower alkyl as described above, such as acetyl.

  The term “cyclo (lower) alkyl” is a cyclic group formed by ring closure of a lower alkyl group containing 3 or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

  The term “cyclo (lower) alkyloxy” means cyclo (lower) alkyl-O—, wherein cyclo (lower) alkyl is as defined above.

  The term “aryl” includes an aromatic hydrocarbon ring group which may be unsubstituted or substituted, and is preferably monocyclic, for example, phenyl, tolyl, xylyl. Substituents include halogen and halogen-substituted lower alkyl groups (wherein the halogen atom and lower alkyl group are as defined above).

  The term “aryloxy” means a group represented by the formula ArO— (wherein Ar is an aryl group as described above).

  As the “heterocycle”, 1 to 4 hetero atoms, preferably 1 to 3, preferably 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to an optionally substituted carbon atom and carbon atom. Examples thereof include 5- to 14-membered, preferably 5- to 10-membered monocyclic to tricyclic, preferably monocyclic heterocyclic groups. Heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl 2-pyrrolinyl group, pyrrolidinyl group, 2-imidazolinyl group, imidazolidinyl group, 2-pyrazolinyl group, pyrazolidinyl group, piperidino group, piperazinyl group, morpholino group, indolyl group, benzothienyl group, quinolyl group, isoquinolyl group, prill group, Examples include quinazolinyl group, carbazolyl group, acridinyl group, phenanthridinyl group, benzimidazolyl group, benzimidazolonyl group, benzothiazolyl group, phenothiazinyl group and the like. Examples of the substituent include halogen and a halogen-substituted lower alkyl group (wherein the halogen atom and the lower alkyl group are as defined above).

  The term “heterocyclicoxy” means a group represented by the formula HcO— (wherein Hc is a heterocyclic group as described above).

  The term “functional derivative” of A includes salts (preferably pharmaceutically acceptable salts), ethers, esters and amides.

  Suitable "pharmaceutically acceptable salts" include conventional non-toxic salts, such as salts with inorganic bases, such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, Magnesium salts, etc.), ammonium salts, salts with organic bases such as amine salts (eg methylamine salts, dimethylamine salts, cyclohexylamine salts, benzylamine salts, piperidine salts, ethylenediamine salts, ethanolamine salts, diethanolamine salts, triethanol) Amine salts, tris (hydroxymethylamino) ethane salts, monomethyl-monoethanolamine salts, procaine salts, caffeine salts, etc.), basic amino acid salts (for example, arginine salts, lysine salts, etc.), tetraalkylammonium salts, etc. . These salts can be prepared, for example, from the corresponding acids and bases by conventional reactions or by salt exchange.

  Examples of ethers include alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl ether, 1-cyclopropylethyl ether, and other lower alkyl ethers, octyl ether, di- Intermediate or higher alkyl ethers such as ethylhexyl ether, lauryl ether and cetyl ether, unsaturated ethers such as oleyl ether and linolenyl ether, lower alkenyl ethers such as vinyl ether and allyl ether, lower alkynyl ethers such as ethynyl ether and propynyl ether, hydroxy Hydroxy (lower) alkyl ethers such as ethyl ether, hydroxyisopropyl ether, methoxymethyl ether, 1 Lower alkoxy (lower) alkyl ethers such as methoxyethyl ether and optionally substituted aryl ethers such as phenyl ether, tosyl ether, t-butylphenyl ether, salicyl ether, 3,4-dimethoxyphenyl ether, benzamide phenyl ether, etc. , Aryl (lower) alkyl ethers such as benzyl ether, trityl ether and benzhydryl ether.

  Esters include methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t-butyl esters, pentyl esters, lower alkyl esters such as 1-cyclopropylethyl ester, lower esters such as vinyl esters and allyl esters. Aliphatics such as lower alkynyl esters such as alkenyl esters, ethynyl esters and propynyl esters, hydroxy (lower) alkyl esters such as hydroxyethyl esters, lower alkoxy (lower) alkyl esters such as methoxymethyl esters and 1-methoxyethyl esters Esters and eg phenyl esters, tolyl esters, t-butylphenyl esters, salicyl esters, 3,4-dimethoxyphenyl esters, benzamides Optionally substituted aryl esters such Eniruesuteru, benzyl ester, trityl ester, aryl (lower) alkyl esters such as benzhydryl ester.

  The amide of A means a group represented by the formula —CONR′R ″ (where R ′ and R ″ are hydrogen, lower alkyl, aryl, alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl). Examples thereof include lower alkylamides such as methylamide, ethylamide, dimethylamide, and diethylamide; arylamides such as anilide and toluidide; and alkyl or arylsulfonylamides such as methylsulfonylamide, ethylsulfonylamide, and tolylsulfonylamide.

  Preferable examples of L and M are hydroxy and oxo, particularly preferably M is hydroxy and L is oxo, and has a five-membered ring structure called a so-called PGE type.

  Preferred examples of A are -COOH, pharmaceutically acceptable salts, esters, amides thereof.

A preferred example of B is —CH ₂ —CH ₂ —, which has a structure called a so-called 13,14-dihydrotype.

Preferred X ₁ and X ₂ are at least one is halogen, preferably both are halogen. Particularly preferred is fluorine, which has a so-called 16,16-difluoro type structure.

Preferred R ₁ is a hydrocarbon having 1 to 10 carbon atoms, particularly preferably a hydrocarbon having 6 to 10 carbon atoms. Furthermore, at least one carbon atom in the aliphatic hydrocarbon may optionally be replaced by oxygen, nitrogen or sulfur.

Specific examples of R ₁ include the following.
_{-CH 2 -CH 2 -CH 2 -CH 2} -CH 2 -CH 2 -,
_{-CH 2 -CH = CH-CH 2} -CH 2 -CH 2 -,
_{-CH 2 -CH 2 -CH 2 -CH 2} -CH = CH-,
_{-CH 2 -C≡C-CH 2 -CH 2} -CH 2 -,
_{-CH 2 -CH 2 -CH 2 -CH 2} -CH (CH 3) -CH 2 -,
_{-CH 2 -CH 2 -CH 2 -CH 2} -O-CH 2 -,
_{-CH 2 -CH = CH-CH 2} -O-CH 2 -,
_{-CH 2 -C≡C-CH 2 -O-} CH 2 -,
_{-CH 2 -CH 2 -CH 2 -CH 2} -CH 2 -CH 2 -CH 2 -,
_{-CH 2 -CH = CH-CH 2} -CH 2 -CH 2 -CH 2 -,
_{-CH 2 -CH 2 -CH 2 -CH 2} -CH 2 -CH = CH-,
_{-CH 2 -C≡C-CH 2 -CH 2} -CH 2 -CH 2 -,
_{-CH 2 -CH 2 -CH 2 -CH 2} -CH 2 -CH (CH 3) -CH 2 -,
_{-CH 2 -CH 2 -CH 2 -CH 2} -CH 2 -CH 2 -CH 2 -CH 2 -,
_{-CH 2 -CH = CH-CH 2} -CH 2 -CH 2 -CH 2 -CH 2 -,
_{-CH 2 -CH 2 -CH 2 -CH 2} -CH 2 -CH 2 -CH = CH-,
_{-CH 2 -C≡C-CH 2 -CH 2} -CH 2 -CH 2 -CH 2 -,
_{-CH 2 -CH 2 -CH 2 -CH 2} -CH 2 -CH 2 -CH (CH 3) -CH 2 -, and the like.

  Preferred Ra is a hydrocarbon having 1 to 10 carbon atoms, particularly preferably 1 to 8 carbon atoms, and may further have 1 or 2 side chains having 1 carbon atom.

  In the above formulas (I) and (II), the arrangement of the ring, α and / or ω chain may be the same as or different from the arrangement of natural PGs. However, the present invention also encompasses mixtures of compounds having a natural configuration and compounds having a non-natural configuration.

  Examples of typical compounds of the present invention are 13,14-dihydro-15-keto-16-mono- or di-fluoro-PGE compounds and derivatives or analogs thereof.

  In the 15-keto-PG compound used in the present invention, keto-hemiacetal equilibrium may occur due to the formation of a hemiacetal between the 11-position hydroxy and the 15-position oxo.

For example, when both X ₁ and X ₂ are halogen, particularly fluorine, it has been confirmed that a bicyclic compound exists as a tautomer.

  When such a tautomer exists, the abundance ratio of both isomers varies depending on the structure of the other moiety or the type of substituent, and in some cases, one isomer may be overwhelmingly present. The 15-keto-PG compound used in the present invention includes both of them.

Furthermore, the 15-keto-PG compounds used in the present invention include bicyclic compounds and analogs or derivatives thereof. The bicyclic compound is represented by the following formula (III).

Ｒ_４’およびＲ_５’は、水素、ヒドロキシ、ハロゲン、低級アルキル、低級アルコキシまたはヒドロキシ（低級）アルキルであり、Ｒ_４’およびＲ_５’は同時にヒドロキシおよび低級アルコキシであることはない。
Ｒ_１は非置換またはハロゲン、アルキル、ヒドロキシ、オキソ、アリールまたは複素環で置換された、二価の飽和または不飽和の低〜中級の脂肪族炭化水素残基であり、脂肪族炭化水素における少なくとも１個の炭素原子は任意に酸素、窒素または硫黄で置換されていてもよい；
Ｒａ’は、非置換またはハロゲン、オキソ、ヒドロキシ、低級アルコキシ、低級アルカノイルオキシ、シクロ（低級）アルキル、シクロ（低級）アルキルオキシ、アリール、アリールオキシ、複素環または複素環オキシで置換された、飽和または不飽和の低〜中級脂肪族炭化水素残基；シクロ（低級）アルキル基；シクロ（低級）アルキルオキシ基；アリール基；アリールオキシ基；複素環基；複素環オキシ基；
Ｒ_３’は水素、低級アルキル、シクロ（低級）アルキル、アリールまたは複素環基］。 [Wherein A represents —CH ₂ OH, —COCH ₂ OH, —COOH or a functional derivative thereof;
X ₁ ′ and X ₂ ′ are hydrogen, lower alkyl, or halogen;
Y is

R ₄ ′ and R ₅ ′ are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy (lower) alkyl, and R ₄ ′ and R ₅ ′ are not simultaneously hydroxy and lower alkoxy.
R ₁ is a divalent saturated or unsaturated low to intermediate aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic ring, and at least in the aliphatic hydrocarbon One carbon atom may be optionally substituted with oxygen, nitrogen or sulfur;
Ra ′ is saturated, unsubstituted or substituted with halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocycle or heterocycleoxy Or unsaturated low to intermediate aliphatic hydrocarbon residue; cyclo (lower) alkyl group; cyclo (lower) alkyloxy group; aryl group; aryloxy group; heterocyclic group; heterocyclic oxy group;
R ₃ ′ is hydrogen, lower alkyl, cyclo (lower) alkyl, aryl or heterocyclic group].

  Furthermore, the compounds used in the present invention may be represented by keto structural formulas or nomenclature, regardless of the presence or absence of isomers, but this is for convenience and attempts to exclude hemiacetal type compounds. Not what you want.

  In the present invention, isomers such as individual tautomers, mixtures or optical isomers, mixtures, racemates and other stereoisomers can be used for the same purpose.

  Some of the compounds used in the present invention are described in US Pat. No. 5,073,569, US Pat. No. 5,166,174, US Pat. No. 5,221,763, US Pat. No. 5,212,324, US Pat. No. 5,739,161, US Pat. All the documents can be produced by the method described in the present specification and the like.

  Subjects to be treated according to the present invention may be mammalian subjects including animals and humans. A pharmaceutical composition comprising a 15-keto-prostaglandin composition as an active ingredient according to the method of the present invention may be administered systemically or locally.

  Usually, the composition is used by methods such as oral administration, intravenous injection (including infusion), subcutaneous administration, rectal administration, and vaginal administration. The amount of active ingredient will vary depending on the type of subject, such as animal or human, the age, sex, weight, symptom to be treated, desired therapeutic effect, administration method, duration of treatment, etc. of the patient to be treated.

  Typically, 15-keto-prostaglandin compounds are administered systemically in 1 to 4 divided doses per day or in a sustained form, with satisfactory effects being obtained at doses of 0.00001 to 100 mg / kg per day.

  The composition of the present invention can be formulated as an orally administered drug, injection drug, instillation drug, topical drug, tablet, sublingual agent, suppository, vaginal suppository composition, and the like.

  The composition of the present invention may be further used in combination with an appropriate physiologically acceptable additive, and the additive includes an excipient, a diluent, an extender, a solvent, a lubricant, an adjuvant, a binder, a disintegration. Agent, coating agent, encapsulating agent, ointment base, suppository base, aerosol, emulsifier, dispersant, suspending agent, thickener, tonicity agent, buffer, soothing agent, antiseptic, antiseptic The components used together with the 15-keto-PG compound, such as an oxidizing agent, a corrigent, a fragrance, a coloring agent, a functional material (eg, cyclodextrin, biodegradable polymer, etc.), a stabilizer, etc. are used generically. The details of these additives may be appropriately selected from those described in general books on pharmaceutics.

  The amount of the 15-keto-prostaglandin compound added to the composition is usually 0.0001 to 10.0% by weight, more preferably 0.001 to 1.0% by weight, although it depends on the form of the composition. is there.

  Solid compositions for oral administration include tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like. In such solid compositions, one or more active substances are mixed with at least one inert diluent. The composition may further contain an additive other than an inert diluent such as a lubricant, a disintegrant, and a stabilizer. Tablets and pills may be coated with a film of a gastric or enteric substance, if necessary, or may be coated with two or more layers. Further, it may be adsorbed on a sustained-release material or may be microencapsulated. Further, it may be a capsule of a substance that can be disintegrated, such as gelatin. Soft capsules can also be prepared by dissolving in a suitable solvent such as fatty acid or its mono-, di- or triglyceride. When quick action is required, it may be a sublingual tablet.

  Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups, elixirs and the like. It may contain a generally used inert diluent such as purified water and ethanol. In addition to the inert diluent, the composition may contain additives such as wetting agents and suspending agents, sweeteners, flavors, fragrances, preservatives and the like.

  The compositions according to the invention include sprays which contain one or more active substances and are formulated by methods known per se.

  Injectable compositions for parenteral administration according to the invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions containing one or more active ingredients. Examples of the aqueous solution and suspension medium include distilled water for injection, physiological saline, and Ringer's solution. Examples of non-aqueous liquid and suspension media include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbates. Such a composition may further contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of bactericides, gas sterilization or radiation sterilization. The injectable composition can also be provided as a sterile powdery composition and used by dissolving in a sterile injectable solvent before use.

  Another form of the composition of the invention is a suppository or vaginal suppository. These suppositories can be prepared by mixing at least one active ingredient of the present invention with a suppository base such as cacao butter, and even if the absorption is improved by using a nonionic surfactant having an appropriate softening temperature. Good.

  In the present invention, the term “treatment” or “treatment” includes all management such as prevention, treatment, symptom reduction, symptom reduction, progression stoppage and the like.

  In the present invention, “drug-induced constipation” is not particularly limited as long as constipation occurs as a side effect due to the use of a drug, and includes cases where constipation is indirectly caused by the use of a drug. Further, constipation caused by an additive or synergistic effect caused by the combined use of a plurality of drugs is also included in the present invention.

Examples of drugs that cause drug-induced constipation to be treated according to the present invention include opioids such as narcotics such as morphine (for example, morphine hydrochloride and MS contin) and codeine (for example, codeine phosphate); Parkinson's disease therapeutic drug (E.g. trihexyphenidyl, levodopa, etc.), antidepressants (e.g., amoxapine, trimipramine, amitriptyline, imipramine, clomipramine, tricyclic antidepressants such as dosrepin, nortriptyline, lofepramine, tetracyclics such as cetipitrine, maprotiline, mianserin Anti-depressants, etc.), anti-cholinergic preparations such as incontinence treatments (eg propanthelin, oxybutynin); antacids (eg aluminum preparations), bone mass increasing agents (eg calcium preparations), diuretics, iron preparations, Calcium antagonist, Ben Diazepine-based agent, (such as chlorpromazine) phenothiazine agent, H 2 _- blockers, pill, etc. tocopherol. In particular, constipation induced by antidepressants such as opioids such as morphine and codeine, and tricyclic antidepressants such as imipramine is effectively treated by the composition according to the invention.

  In the present invention, “subject suffering from or highly likely to suffer from constipation induced by a drug” refers to a subject who has been administered a drug causing constipation as described above and actually developed constipation, and as a side effect This includes both subjects who are likely to become constipated by administration of a drug, such as subjects who have been administered a drug such as an opioid or antidepressant that is known to have a high probability of developing constipation.

  In the present invention, one kind of active ingredient can be included alone in the preparation, or two or more kinds of active ingredients can be used in combination. When a plurality of active ingredients are used in combination, the content of each can be appropriately increased or decreased in consideration of their therapeutic effects and safety.

  Furthermore, in the composition of the present invention, other pharmacologically active ingredients can be appropriately contained unless they are contrary to the object of the present invention.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this does not limit this invention.

Antagonism against morphine-induced constipation Fifteen ICR male mice were fasted overnight in a breeding cage with a wire grid bottom to avoid feces. After intraperitoneal administration of 5 mg / kg morphine hydrochloride (Takeda Pharmaceutical Co., Ltd., Osaka, Japan) to animals, immediately 0.1 mL of graphite marker (2: 1 mixture of Pilot INK-30-B and 10% tragacanth mucilage) And 5 mL / kg of medium (0.01% polysorbate 80 and 0.5% ethanol-containing physiological saline) or 5 mL of the test substance (13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ ) / Kg was administered orally at doses of 1, 10 and 100 μg / kg. In the normal control group, morphine hydrochloride was not administered, and only the graphite marker and the vehicle were orally administered at the same dose. 150 minutes after administration of the graphite marker, the animal was dislocated after cervical dislocation, and the presence of the graphite marker in the cecum was examined. A case where a graphite marker was present in the cecum was regarded as positive (positive example).

  Table 1 shows the number of animals in which graphite markers were observed in the cecum of each test group (number of positive animals) and the ratio thereof.

ａ）陽性例数：盲腸内に黒鉛マーカーが認められた動物数
モルヒネ＋媒体群に対し、^＊ｐ＜０．０５、^＊＊ｐ＜０．０１（χ^２検定）

a) Positive Example stars to the number of animals morphine + vehicle group which graphite marker was found in the ^{caecum, * p <0.05, ** p} <0.01 (χ 2 test)

  In the normal group, graphite markers were observed in the cecum in all 15 animals (100%).

  In the morphine + vehicle group, graphite markers were observed in the cecum in 3/15 cases (20%), and the number of positive animals was significantly reduced compared to the normal group, that is, constipation induced by morphine treatment was observed. .

  In the test substance administration group, 9/15 cases (60%), 13/15 cases (87%) and 14/15 (93%) were administered in the test substance 1, 10 or 100 μg / kg group in a dose-dependent manner. Immediately after, a graphite marker was observed in the cecum. In the test substance group, antagonism was significantly observed against constipation induced by morphine compared to the control (morphine + vehicle) group.

  From the above results, it was revealed that the substance of the present invention has an antagonistic action against opioid-induced constipation even at a low dose of 1 μg / kg.

(Comparative example)
Antagonism against morphine-induced constipation The effects of laxatives (sennoside and picosulfate sodium) used clinically for the treatment of constipation in patients receiving morphine were confirmed on morphine-induced constipation.

  Sennoside (Tablet: Novartis Pharma Co., Ltd., Tokyo, Japan) was powdered in a mortar, and then a 0.5% tragacanth solution was used to form a suspension having a concentration required for the intended dose level. Picosulfate sodium (solution: Teijin Limited, Tokyo, Japan) was diluted with physiological saline.

  As the dose level of each test substance, clinical daily dose (clinical daily dose: sennoside 24 mg, picosulfate sodium 7.5 mg / body weight 50 kg, 0.48 mg / kg, 0.15 mg / kg, respectively) and 10 Double amount was set. Each medium used was a diluted solution.

  The test method was the same as in Example 1.

  Table 2 (sennoside) and Table 3 (picosulfate sodium) show the number of animals (number of positive animals) in which graphite markers were observed in the cecum of each test group.

ａ）陽性例数：盲腸内に黒鉛マーカーが認められた動物数
モルヒネ＋媒体群に対し、^＊＊ｐ＜０．０１（χ^２検定）

a) Number of positive cases: Number of animals with graphite marker in the cecum for morphine + vehicle group ^** p <0.01 (χ ² test)

ａ）陽性例数：盲腸内に黒鉛マーカーが認められた動物数
モルヒネ＋媒体群に対し、^＊ｐ＜０．０５（χ^２検定）

a) Number of positive cases: Number of animals with graphite marker in the caecum ^* P <0.05 (chi ² test) for morphine + vehicle group

  Laxatives (sennoside and picosulfate sodium) that are commonly used to treat constipation in patients receiving morphine are effective against morphine-induced constipation at doses equivalent to the clinical daily dose and 10 times its dose. I couldn't.

  From the above results, it was suggested that ordinary laxatives having a laxative effect do not necessarily show effective antagonism against opioid-induced constipation, and it is difficult to sufficiently control constipation.

Effect on analgesic activity The tail of an ICR male mouse fasted overnight in a breeding cage with a wire grid bottom to avoid fecal feeding was pinched with a clamp, and the reaction time until attack, biting or crying was measured. Eighteen animals showing reaction times within 2 seconds were used as test animals. Tests in which morphine hydrochloride (Takeda Pharmaceutical Co., Ltd., Osaka, Japan) 5 mg / kg was intraperitoneally administered to animals, and immediately dissolved in a medium (saline containing 0.01% polysorbate 80 and 0.5% ethanol) or medium. The substance (13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ ) 1, 10 or 100 μg / kg was orally administered at a dose of 5 mL / kg. In the normal control group, morphine hydrochloride was not administered, and only the vehicle was orally administered at the same dose.

  At 30, 60, 90, 120 and 150 minutes after drug administration, the tail of the animal was pinched with a clamp and the reaction time was measured. At this time, in order to avoid damage to the tissue of the tail, the measurement was stopped when no reaction was observed for 10 seconds or more after application of CLEMME, and the reaction time was 10 seconds. The results are shown in Table 4.

  The reaction time before drug administration was about 1 second in each group, and there was no difference between the groups.

  The reaction time in the normal group did not change at any time after vehicle administration compared to before administration.

  In the morphine + vehicle group, a significant increase in the reaction time was observed 30 and 60 minutes after morphine treatment compared to the normal group, and the reaction time tended to increase even after 90 minutes. The analgesic effect of morphine almost disappeared after 120 and 150 minutes.

  In the morphine + test substance group, a significant increase in the reaction time was observed in any group compared to the normal group. In the morphine + test substance group, the reaction time was comparable to that observed for the morphine + vehicle group.

  There was no significant difference between the reaction times of the morphine + vehicle administration group and the morphine + test substance group, and the test substance did not affect the analgesic effect of morphine.

  From the above results, it has been clarified that the substance of the present invention does not affect the analgesic action of opioids even at a high dose of 100 μg / kg.

Antagonism against imipramine (tricyclic antidepressant) -induced constipation Ten ICR male mice were fasted overnight in a breeding cage with a wire grid bottom to avoid feces. Immediately after intraperitoneal administration of imipramine hydrochloride (Wako Pure Chemicals, Osaka, Japan) 60 mg / kg, 0.1 mL carbon marker (10% carbon powder suspension in 5% gum arabic) and medium (0.01% Polysorbate 80 and 0.5% ethanol-containing physiological saline) or a test substance (13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ ) was orally administered at a dose of 5 mL / kg. In the normal control group, imipramine was not administered, and only the carbon marker and vehicle were orally administered at the same dose. 150 minutes after administration of the carbon marker, the animals were laparotomized after cervical dislocation and examined for the presence of carbon markers in the cecum. A case where a carbon marker was present in the cecum was regarded as positive (positive example).

  Table 5 shows the number of animals in which carbon markers were found in the cecum of each test group (number of positive animals) and the ratio thereof.

  These results indicate that the substances of the invention antagonize imipramine-induced constipation.

ａ）陽性例数：盲腸内に炭素マーカーが認められた動物数
イミプラミン＋媒体群に対し、^＊＊ｐ＜０．０１（χ^２検定）

a) Number of positive cases: Number of animals with carbon marker in cecum for imipramine + vehicle group ^** p <0.01 (χ ² test)

(Comparative example)
Antagonism against imipramine (tricyclic antidepressant) -induced constipation The effect of laxatives (sennoside) clinically used by patients for the treatment of constipation on imipramine-induced constipation was investigated. Sennoside preparation and dose levels were the same as described in Example 2. The experimental method was the same as that described in Example 4.

  Table 6 shows the number of animals in which carbon markers were observed in the cecum of each test group (number of positive animals) and the ratio thereof.

  These results indicate that sennoside has no effect on imipramine-induced constipation.

ａ）陽性例数：盲腸内に炭素マーカーが認められた動物数
イミプラミン＋媒体群に対し、^＊＊ｐ＜０．０１（χ^２検定）

a) Number of positive cases: Number of animals with carbon marker in cecum for imipramine + vehicle group ^** p <0.01 (χ ² test)

Claims (8)

General formula (II):

[Wherein L is oxo, M is hydroxy;
A is, -COOH or a salt, ester or amide;
B represents —CH ₂ —CH ₂ —;
X ₁ and X ₂ are hydrogen, lower alkyl or halogen, and at least one of X ₁ and X ₂ is halogen;
R ₁ represents an unsubstituted divalent saturated or unsaturated aliphatic hydrocarbon having a straight chain or branched chain having 1 to 14 carbon atoms (provided that the side chain has 1 to 3 carbon atoms);
R ₂ is a single bond or lower alkylene; and
R ₃ is lower alkyl]
A composition for treatment of drug-induced constipation with an opioid compound or an anticholinergic agent, which comprises a 13,14-dihydro-15-keto-16-mono- or di-halogen-prostaglandin E compound represented by the formula:   13,14-Dihydro-15-keto-16-mono- or di-halogen-prostaglandin E compound is 13,14-dihydro-15-keto-16-mono- or di-fluoro-prostaglandin E compound The composition according to claim 1.   The 13,14-dihydro-15-keto-16-mono- or di-halogen-prostaglandin E compound is a 13,14-dihydro-15-keto-16,16-di-fluoro-prostaglandin E compound. The composition according to claim 1. 13,14-dihydro-15-keto-16-mono - or di - halogen - prostaglandin E compound is 13,14-dihydro-15-keto-16,16-difluoro - claim prostaglandin _{E 1} The composition according to 1.   The composition according to any one of claims 1 to 4, wherein the drug that induces constipation is an opioid compound.   The composition according to claim 5, wherein the opioid compound is a morphine compound or a codeine compound.   The composition according to any one of claims 1 to 4, wherein the drug that induces constipation is an anticholinergic agent.   The composition according to claim 7, wherein the anticholinergic agent is a tricyclic antidepressant.